Modern high calorie diets and reduced physical activity promote obesity, which has become an alarming public health concern. The wide-ranging, health-related impacts of obesity include cardiovascular disease, metabolic syndrome, non-alcoholic fatty liver disease, some forms of cancer, and Type 2 diabetes in particular, which is a disorder of insulin production and action that has life-threatening consequences. The worsening problem of obesity predicts that these co-morbidities will strain or break health care delivery systems worldwide. It is a matter of some urgency that the genes that couple obesity to these diseases remain incompletely understood. However, it has been appreciated for some time that certain obese individuals are at reduced risk for cardiovascular disease and Type 2 diabetes. These [unreadable]metabolically healthy but obese[unreadable] (MHO) patients are important because of the opportunity they provide to increase our understanding of the etiology of obesitydriven diabetes. We have recently published our finding that a dual bromodomain protein and transcriptional co-activator called Brd2 is an unexpected yet important regulator of obesity and glucose homeostasis. Mice deficient for Brd2 develop extraordinary obesity with body weights approaching 100g, but never develop insulin resistance (IR) or Type 2 diabetes, suggesting that they offer a unique animal model for these MHO patients. Like MHO patients, Brd2-deficient mice show reduced inflammatory processes, which we hypothesize protect them from IR. Their white adipose tissue (WAT) is not infiltrated by inflammatory macrophages, and bone marrow-derived macrophages underproduce pro-inflammatory cytokines. Interestingly, Brd2 ordinarily binds to PPAR-gamma and opposes its transcriptional activity, thus, Brd2 deficiency resembles thiazolidinedione action. Thiazolidinediones are insulin-sensitizing drugs that act as agonists of PPAR-gamma. We hypothesize that PPAR-gamma-dependent processes, including adipogenesis and macrophage M2 polarization, are strongly potentiated in these mice. Preliminary gene expression profiling studies of human abdominal adipocytes establish that PPAR-gamma levels are negatively correlated with Brd2, matching the animal model and indicating functional conservation. Thus, studies of these mice are likely to be highly informative of novel, MHO-specific pathways that could be exploited to treat obese patients at serious risk for Type 2 diabetes. Based on these preliminary data we structure our approach in three Specific Aims: 1. Define cellular and molecular mechanisms by which Brd2 deficiency protects WAT against the pro-inflammatory (M1) phenotype of adipose tissue macrophages. 2. Use co-culture of macrophage and adipocyte models to determine whether Brd2 deficiency protects adipocytes from cytokine-driven IR or promotes M2 polarization of macrophages, or both. 3. Determine the mechanism of Brd2 transactivation of the TNF-alpha gene. The molecular insights we expect to attain will open new avenues for treatment of IR and metabolic syndrome, and will allow the intrinsic protections of MHO patients to be extended to the general population of obese and overweight individuals.